While penicillin-susceptible Staphylococcus aureus bacteremia remains relatively uncommon, there has been significant debate as to whether the anti-staphylococcal penicillins (oxacillin, nafcillin, flucloxacillin, cloxacillin) that are resistant to penicillinase-mediated degradation should be given for PSSA over penicillin due to theoretical concerns for misclassifying low-level penicillinase production in vitro.
As a part of the S. aureus Network Adaptive Platform, a randomized open-label trial of benzylpenicillin (penicillin G) versus flucloxacillin or cloxacillin for PSSA bacteremia was conducted across 67 hospitals worldwide and recently published in The Lancet.
Between February 2022 and June 2024, 156 patients were assigned to benzylpenicillin and 125 patients to flucloxacillin or cloxacillin. Penicillin susceptibility was determined clinically by phenotypic disk diffusion (vast majority of sites) or PCR for blaZ. Patients were enrolled within 72 hours of first positive blood culture, and duration of therapy was at the discretion of the treating provider (but was at least 14 days for uncomplicated bacteremia and 28-42 days for complicated bacteremia), with subsequent randomization to an early oral switch study at either 7 or 14 days for eligible candidates. Total median duration of antibiotic therapy was 39 days in the benzylpenicillin group and 42 days in the flucloxacillin/cloxacillin group.
Ninety-day mortality was 14% in the benzylpenicillin group versus 21% in the flucloxacillin/cloxacillin group, with a posterior probability of benzylpenicillin noninferiority and superiority of 96.1% and 88.9%, respectively. Benzylpenicillin was also associated with half the rate of acute kidney injury of the flucloxacillin/cloxacillin group.
This study shows that benzylpenicillin can be used effectively for PSSA bacteremia with a lower rate of adverse events than anti-staphylococcal penicillins, but the authors note that their findings should not be extended to sites that only do automated penicillin susceptibility testing.
As with the recent SNAP analysis of cefazolin versus flucloxacillin or cloxacillin published in The New England Journal of Medicine, presence and typing of blaZ will be reported separately and could reveal important insights, as there was some signal in the recent CloCeBa study where noninferiority of cefazolin was not met among those with type A blaZ isolates. There may eventually be a role for adding blaZ type to rapid molecular diagnostic panels for identification of S. aureus in blood cultures pending this work.
(The Staphylococcus aureus Network Adaptive Platform Trial Group. Lancet. 2026;408(10550):141-152.)
